Abstract
Aquaporin-9 (AQP9) is a membrane protein channel that is permeable to a range of small solutes, including glycerol, urea and nucleobases. Expression of AQP9 in normal brain is limited, while widespread AQP9 expression has previously been reported in human glioblastoma. However, the specific cellular expression of AQP9 in glioblastoma remains unclear. In this study, we have examined microarrays to corroborate AQP9 mRNA expression in glioma. These analyses suggested that AQP9 mRNA expression in glioblastoma is primarily explained by tumor infiltration with AQP9 expressing leukocytes. Immunolabeling confirmed that within tumor regions, AQP9 was expressed in CD15+ and Calgranulin B+ leukocytes, but also in larger cells that morphologically resembled glioma cells. Specificity of immunoreagents was tested in recombinant cell lines, leukocyte preparations, and sections of normal human brain and liver tissue. Apparent AQP9+ glioma cells were frequently observed in proximity to blood vessels, where brain tumor stem cells have been observed previously. A fraction of these larger AQP9 expressing cells co-expressed the differentiated astrocyte marker GFAP. AQP9 expressing glioma cells were negative for the brain tumor stem cell marker CD15, but were observed in proximity to CD15+ glioma cells. AQP9 expression may therefore require signals of the perivascular tumor environment or alternatively it may be restricted to a population of glioma stem cell early progenitor cells.
Highlights
Aquaporin-9 (AQP9) is a member of the major intrinsic protein family
We found that AQP9 mRNA was co-regulated with several transcripts encoding components of the innate immune response, such as complement components and molecules known to mediate responses to bacterial lipopolysaccharide (LPS)
These mRNAs encode proteins forming calgranulin A-calgranulin B dimers, which can act as ligands for the toll-like receptor 4 (TLR4) LPS receptor [16]
Summary
Aquaporin-9 (AQP9) is a member of the major intrinsic protein family. It was originally identified in an expression screen for a putative hepatocyte urea channel [1]. AQP9 was found to be highly permeable to glycerol, adenine and uracil as well as moderately permeable to lactate and b-hydroxybutyrate in the same study [1]. We have recently demonstrated the physiological importance of AQP9 in hepatocyte gluconeogenesis from glycerol [2]. AQP9 expression has been described in several tissues, including normal brain. The identified locations of AQP9 expression in murine, rat and primate brain were not entirely consistent between studies: AQP9 expression was found in mouse brain in astrocytes, in rat brain tanycytes, ependymal cells, glia limitans and catecholaminergic neurons, as well as in primates in astrocytes and catecholaminergic neurons [3,4,5,6]
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